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Abstract Introduction The 2021 Canadian Cardiovascular Society (CCS) guidelines recommend intensive low-density lipoprotein cholesterol (LDL-C) reduction for patients with atherosclerotic cardiovascular disease (ASCVD). For patients above LDL-C threshold on maximally tolerated statins, adding ezetimibe and/or a proprotein convertase subtilisin/kexin type 9 inhibitor (PCSK9i) is recommended. This population-based, real-world study examined cardiovascular (CV) events in patients with ASCVD who are on statins and above current guideline threshold LDL-C levels. Methods Using administrative health data in Alberta, Canada, we identified patients with myocardial infarction (MI), ischemic stroke (IS), or peripheral artery disease with LDL-C > 1.8 mmol/L on statins between April 1, 2010 and March 31, 2016. Exploratory subgroups included very high-risk patients with ASCVD shown to derive the most benefit from PCSK9i intensification as identified by the CCS guidelines, including those with acute coronary syndrome (ACS) or recent MI. Frequencies and rates of individual and composite CV events (primary outcome: MI, IS, hospitalization for unstable angina, coronary revascularization, cardiovascular death; secondary outcome: MI, IS, CV death) were calculated over follow-up. Results The study included 32,984 patients with a mean (standard deviation) follow-up of 40.8 (21.0) months. Overall, 17.7% and 15.6% experienced a primary and secondary outcome, respectively, with rates of 5.58 and 4.83 per 100 patient-years, respectively. CV death and MI were the most common events. Subgroups with recurrent MI and comorbid diabetes exhibited higher CV event rates (23.6% and 22.2% had a primary outcome, respectively). Rates of CV events were notably high in patients with ACS or recent MI (49.4% and 54.0% had a primary outcome, respectively). Conclusion This real-world study confirms that statin-treated high-risk patients with ASCVD and above-threshold LDL-C levels have substantial incidence of recurrent CV events. These findings reinforce the opportunity for lipid-lowering therapy intensification in high-risk patients to levels below guideline-recommended threshold in order to reduce CV risk.

Elevated low-density lipoprotein cholesterol (LDL-C) is a major causal factor for atherosclerotic cardiovascular disease (ASCVD), the leading cause of mortality worldwide. Statins are the recommended first-line lipid-lowering therapy (LLT) for patients with primary hypercholesterolemia and established ASCVD, with LLT intensification recommended in the substantial proportion of patients who do not achieve levels below guideline-recommended LDL-C thresholds with statin treatment alone. The proprotein convertase subtilisin/kexin type 9 inhibitor monoclonal antibody evolocumab has demonstrated significant LDL-C reductions of >60% in the clinical trial and open-label extension settings, with LDL-C reductions observed early post-evolocumab initiation and maintained long term, during up to 8.4 years of follow-up. Evolocumab therapy, when added to a statin, also conferred a significant reduction in major cardiovascular (CV) events, including a 20% reduction in the composite of CV death, myocardial infarction (MI), or stroke. The absolute benefits were enhanced among various patient types at high and very high risk for secondary ASCVD (e.g., with recent MI, multiple events or peripheral artery disease). Importantly, evolocumab treatment resulted in incremental CV risk reductions during the extended follow-up, including a 23% reduction in CV mortality and no apparent LDL-C level below which there is no further CV risk reduction. Hence, the evolocumab clinical data support the need for early and significant LDL-C lowering, especially in vulnerable ASCVD patients, in order to derive the greatest benefit in the long term. Importantly, evolocumab had no impact on any treatment emergent adverse events apart from a small increase in local injection site reactions. A growing body of real-world evidence (RWE) for evolocumab in heterogeneous populations is consistent with the trial data, including robust LDL-C reductions below guideline-recommended thresholds, a favourable safety profile even at the lowest levels of LDL-C achieved, and a high treatment persistence rate of >90%. Altogether, this review highlights findings from 50 clinical trials and RWE studies in >51,000 patients treated with evolocumab, to demonstrate the potential of evolocumab to address the healthcare gap in LDL-C reduction and secondary prevention of ASCVD in a variety of high- and very high-risk patients.

Objectives: REDUCE-IT showed that icosapent ethyl (IPE) improved cardiovascular (CV) outcomes in participants with established CV disease (CVD) or type 2 diabetes (T2D) and at least one additional risk factor plus mild-moderate hypertriglyceridemia and reasonably controlled low-density lipoprotein cholesterol (LDL-C). As the generalizability of REDUCE-IT has not been investigated in a T2D population with established CVD, this post hoc analysis investigated how many participants from EMPA-REG OUTCOME, which tested the effects of empagliflozin versus placebo on CV outcomes in participants with T2D and CVD, would have been eligible for IPE treatment, and whether CV outcomes differed based on eligibility for IPE treatment. Methods: Participants from EMPA-REG OUTCOME were screened for inclusion using both REDUCE-IT-like criteria (baseline statin therapy, triglycerides 135–499 mg/dL and LDL-C 41–100 mg/dL) and slightly amended FDA indication criteria (triglycerides ≥150 mg/dL). Analyses were conducted to characterize the study population and CV outcomes in participants eligible for IPE versus those not eligible for IPE. Results: Of the 7020 participants from EMPA-REG OUTCOME, 1810 (25.8%) fulfilled REDUCE-IT criteria and 3182 (45.3%) fulfilled FDA criteria for IPE treatment. Treatment effects of empagliflozin versus placebo on CV and kidney outcomes and mortality were consistent in participants meeting REDUCE-IT and FDA criteria and those who did not. Conclusions: These results indicate that a sizable proportion of patients with diabetes and established CVD, such as those in EMPA-REG OUTCOME, may be eligible for IPE treatment to lower residual CV risk. Treatment benefit with empagliflozin was consistent, regardless of REDUCE-IT or FDA eligibility criteria.

Abstract Background The estimated glomerular filtration rate (eGFR) and the albumin-to-creatinine ratio (ACR) are risk factors for diabetes-related outcomes. A composite that captures information from both may provide a simpler way of assessing risk. Methods 9115 of 9901 Researching Cardiovascular Events with a Weekly Incretin in Diabetes (REWIND) participants with both an ACR and eGFR at baseline were included in this post hoc epidemiologic analysis. The hazard of higher baseline levels of 1/eGFR and natural log transformed ACR (calculated as ln [ACR × 100] to eliminate negative values) and their interaction for incident major adverse cardiovascular events (MACE), kidney outcomes, and deaths was estimated. The hazard of the geometric mean of these two baseline measures (the kidney disease index or KDI) was also assessed. Results A non-linear relationship was observed between 1/eGFR and all three outcomes, and between ln [ACR × 100] and the kidney outcome. There was also a negative interaction between these two risk factors with respect to MACE and death. Conversely, a linear relationship was noted between the KDI and all three outcomes. People in the highest KDI fifth experienced the highest incidence of MACE, death, and the kidney outcome (4.43, 4.56, and 5.55/100 person-years respectively). C statistics for the KDI were similar to those for eGFR and albuminuria. Conclusions The KDI combines the baseline eGFR and ACR into a novel composite risk factor that has a simple linear relationship with incident serious outcomes in people with diabetes and additional CV risk factors. Trial Registration clinicaltrials.gov NCT01394952.

Patients with cerebrovascular disease (CeVD) have been shown to benefit from lipid-lowering therapies, but guideline-recommended levels of low-density lipoprotein cholesterol (LDL-C) are often not attained with statin treatment alone. The ORION-9, ORION-10, and ORION-11 trials evaluated the efficacy and safety of inclisiran in 3660 primary and secondary prevention patients with hyperlipidemia despite maximum tolerated statin treatment. This pooled post hoc analysis comprised 202 randomized patients from those trials with established CeVD who had received either 284 mg inclisiran (equivalent to 300 mg inclisiran sodium, n = 110) or placebo (n = 92) on Days 1, 90, and 6-monthly thereafter up to Day 540. At baseline, mean (SD) LDL-C was 108.4 (34.3) mg/dL and 110.5 (35.3) mg/dL in inclisiran and placebo arms, respectively. Inclisiran produced a mean (95% CI) placebo-corrected percentage change in LDL-C from baseline to Day 510 of –55.2 (–64.5 to –45.9; p

Abstract Background Type-2 diabetes (T2D), chronic kidney disease, and heart failure (HF) share epidemiological and pathophysiological features. Although their prevalence was described, there is limited contemporary, high-resolution, epidemiological data regarding the overlap among them. We aimed to describe the epidemiological intersections between T2D, HF, and kidney dysfunction in an entire database, overall and by age and sex. Methods This is a cross-sectional analysis of adults ≥ 25 years, registered in 2019 at Maccabi Healthcare Services, a large healthcare maintenance organization in Israel. Collected data included sex, age, presence of T2D or HF, and last estimated glomerular filtration rate (eGFR) in the past two years. Subjects with T2D, HF, or eGFR

Abstract Aims In the EMPA‐REG OUTCOME trial, in patients with type 2 diabetes and established atherosclerotic cardiovascular (CV) disease, empagliflozin vs. placebo reduced the risk of hospitalization for heart failure (HHF) by 35%, CV death/HHF by 34%, and CV death by 38%, with an early separation of the cumulative incidence curves. We explored at what time point after randomization these benefits became apparent. Methods and results We expressed time trajectories for the effect of pooled empagliflozin doses vs. placebo on HHF, CV death/HHF, and CV death based on hazard ratios (95% confidence interval) and calculated the hazard ratio on the day the effect reached significance using Cox proportional hazards models. Overall, 7020 patients aged ≥18 years were treated with empagliflozin 10 mg (N = 2345), empagliflozin 25 mg (N = 2342), or placebo (N = 2333) once daily in addition to standard of care. Mean age (years ± SD) was 63.1 ± 8.6, and 72% were male. The benefit of empagliflozin on CV death first reached statistical significance on Day 59 (HR [95% confidence interval]) (0.28 [0.08, 0.96], P = 0.0424) and was generally sustained throughout the trial (overall 0.62 [0.49, 0.77], P

Abstract During the last decade we experienced a surge in the number of glucose lowering agents that can be used to treat patients with type 2 diabetes. Especially important are the discoveries that sodium glucose co-transporter type 2 inhibitors (SGLT2i) and glucagon-like peptide-1 receptor agonists (GLP-1 RA) improve patients’ cardiovascular and renal outcomes. Accordingly, various medical associations have updated their guidelines for the treatment of diabetes in this new era. Though not agreeing on every issue, these position-statements generally share a detailed and often complex workflow that may be too complicated for the busy and overworked primary care setting, where the majority of patients with type 2 diabetes are managed in many countries. Other guidelines, generally those from the cardiology associations focus primarily on the population of patients with high risk for or pre-existing cardiovascular disease, which represent only the minority of patients with type 2 diabetes. We believe that we should re-define SGLT2i and GLP-1 RA as diabetes/disease modifying drugs (DMDs) given the recent evidence of their cardiovascular and renal benefits. Based on this definition we have designed a SIMPLE approach in order to assist primary care teams in selecting the most appropriate therapy for their patients. We believe that most subjects newly diagnosed with type 2 diabetes should initiate early combination therapy with metformin and a prognosis changing DMD. The decision whether to use GLP-1 RA or SGLT2i should be made based on specific patient’s risk factors and preferences. Importantly, DMDs are known to have a generally safe side-effect profile, with lower risk for hypoglycemia and weight gain, further promoting their wider usage. Early combination therapy with DMDs may improve the multiple pathophysiological abnormalities responsible for type 2 diabetes and its complications, thus resulting in the greatest long term benefits.

A recent acute coronary syndrome provides an opportunity to optimise secondary prevention strategies to reduce the risk of future cardiovascular events. This review provides an updated synopsis of current evidence-based approaches. New clinical trial data on the use of antiplatelet and anticoagulants allow choices of the selection and duration of treatment. Lipid lowering after an acute coronary syndrome is now enhanced, with proprotein convertase subtilisin-kexin type 9 inhibitors providing added benefit on top of statin and ezetimibe treatment in high-risk patients. In addition, a recent trial of icosapent ethyl, a highly purified ethyl ester of eicosapentaenoic acid, addresses residual risk in patients with elevated triglycerides already treated with statins. The use of both sodium-glucose co-transporter 2 inhibitors and glucagon-like peptide-1 receptor agonists in patients with type 2 diabetes reduces cardiovascular events independently of glucose lowering. Résumé: La survenue récente d’un syndrome coronarien aigu offre l’occasion d’optimiser les stratégies de prévention secondaire en vue de réduire le risque d’événements cardiovasculaires futurs. Le présent article de synthèse offre une vue d’ensemble actualisée des approches contemporaines fondées sur des données probantes. Les nouvelles données d’essais cliniques sur l’utilisation d’antiplaquettaires et d’anticoagulants permettent de choisir un traitement et sa durée. La réduction des lipides après la survenue d’un syndrome coronarien aigu se trouve maintenant améliorée, les bienfaits des inhibiteurs de la proprotéine convertase subtilisine/kexine de type 9 s’ajoutant à ceux du traitement par des statines et l’ézétimibe chez les patients à haut risque. En outre, un essai récent portant sur l’icosapent éthyl, un ester éthylique hautement purifié de l’acide eicosapentaénoïque, aborde le risque résiduel chez les patients présentant une hypertriglycéridémie déjà traités par des statines. L’utilisation d’inhibiteurs du cotransporteur sodium-glucose de type 2 et d’agonistes des récepteurs du peptide-1 apparenté au glucagon chez les patients atteints de diabète de type 2 limite les événements cardiovasculaires indépendamment de la diminution de la glycémie.

Background: Despite the widespread use of statins, approximately 40% to 50% of Canadian patients with known cardiovascular disease do not achieve the low-density lipoprotein cholesterol (LDL-C) goal. Guidelines Oriented Approach to Lipid lowering (GOAL) is an investigator-initiated study aiming to ascertain the use of second- and third-line therapy and its impact on LDL-C goal achievement in a real-world setting. Methods: GOAL enrolled patients with clinical vascular disease or familial hypercholesterolemia and LDL-C > 2.0 mmol/L despite maximally tolerated statin therapy. During follow-up, physicians managed patients as clinically indicated but with online reminders of guideline recommendations. Results: Of 2009 patients enrolled (median age 63 years, 42% were female), baseline total cholesterol was 5.5 ± 1.4 mmol/L, LDL-C was 3.3 ± 1.3 mmol/L, non–high-density lipoprotein cholesterol was 4.1 ± 1.4 mmol/L, high-density lipoprotein cholesterol was 1.3 ± 0.4 mmol/L, and triglycerides were 2.0 ± 1.5 mmol/L. Lipid-lowering therapy used at baseline was statin therapy in 76% (with 24% statin intolerant) and ezetimibe in 25%. During follow-up, the proportion of patients achieving an LDL-C level of < 2.0 mmol/L increased significantly to 50.8% as a result of additional lipid-lowering therapy. Patients achieving the recommended LDL-C level were more likely to not be statin intolerant (83.8% vs 70.7%, P 2,0 mmol/l malgré un traitement par une statine à la dose maximale tolérée, ont été inscrits à l’étude GOAL. Pendant la période de suivi, les médecins prenaient en charge le traitement de leurs patients selon les besoins cliniques, mais en recevant par voie électronique des rappels des recommandations formulées dans les lignes directrices. Résultats: Chez les 2009 patients inscrits à l’étude (âge médian : 63 ans; femmes : 42 %), les taux initiaux moyens étaient les suivants : cholestérol total initial : 5,5 ± 1,4 mmol/l, C-LDL : 3,3 ± 1,3 mmol/l, C non HDL (autre que le cholestérol à lipoprotéines de haute densité) : 4,1 ± 1,4 mmol/l, C-HDL (des lipoprotéines de haute densité) : 1,3 ± 0,4 mmol/l et triglycérides : 2,0 ± 1,5 mmol/l. Le traitement hypolipidémiant utilisé au début de l’étude était composé d’une statine chez 76 % des participants (24 % des patients ne toléraient pas les statines) et d’ézétimibe chez 25 %. Pendant la période de suivi, la proportion de patients atteignant un taux de C-LDL < 2,0 mmol/l a augmenté de façon significative, jusqu’à atteindre 50,8 %, en raison de l’utilisation d’hypolipidémiants additionnels. Les patients atteignant les taux cibles de C-LDL étaient plus susceptibles de ne pas être intolérants aux statines (83,8 % vs 70,7 %, p < 0,0001) et de prendre un type et une dose de statine hautement efficaces (52,4 % vs 35,9 %, p < 0,0001). Les trois principales raisons évoquées pour expliquer le fait de n’avoir pas eu recours au traitement recommandé par l’ézétimibe étaient le refus du patient (33 %), l’absence de besoin (22 %) et l’intolérance (20 %), alors que dans le cas des inhibiteurs de la PCSK9, les raisons données étaient plutôt le coût élevé (26 %), l’absence de besoin (27 %) et le refus du patient (25 %). Conclusion: Les résultats de cette étude montrent la faisabilité de l’optimisation de la prise en charge, qui entraîne l’atteinte des taux de C-LDL recommandés dans les lignes directrices. Ces résultats pourraient se traduire par des réductions de la morbidité et de la mortalité d’origine cardiovasculaire chez les patients canadiens.

Abstract Background Mixed dyslipidemia [elevated non-high-density lipoprotein cholesterol (non-HDL-C) and triglycerides (TGs), and decreased HDL-C] is common in type 2 diabetes mellitus (T2DM) and is associated with increased cardiovascular risk. Non-HDL-C and apolipoprotein B (ApoB) are the preferred therapeutic targets for mixed dyslipidemia. Alirocumab is a monoclonal antibody to proprotein convertase subtilisin/kexin type 9 (PCSK9) that effectively reduces low-density lipoprotein cholesterol (LDL-C), non-HDL-C, ApoB, and lipoprotein(a) (Lp[a]), and is well-tolerated in individuals with T2DM. Methods The previously reported open-label ODYSSEY DM-DYSLIPIDEMIA trial data demonstrated the effects of alirocumab on individuals with non‐HDL-C ≥ 100 mg/dL and TGs ≥ 150 and

Abstract Background To examine the impact on glycemic control of achieving postprandial glucose (PPG) target with lixisenatide, a once-daily glucagon-like peptide-1 receptor agonist approved in the US, in patients with uncontrolled type 2 diabetes (T2D) on basal insulin, an agent that primarily targets fasting plasma glucose. Methods A post hoc pooled analysis was conducted using clinical trial data extracted from the intent-to-treat subpopulation of patients with T2D who participated in the 24-week, phase 3, randomized, double-blind, placebo-controlled, 2-arm parallel-group, multicenter GetGoal-L (NCT00715624), GetGoal-Duo 1 (NCT00975286) and GetGoal-L Asia trials (NCT00866658). Results Data from 587 lixisenatide-treated patients and 484 placebo-treated patients were included. Patients on lixisenatide were more likely to achieve a PPG target of

Summary: The coronavirus disease 2019 (COVID-19) pandemic remains a source of considerable morbidity and mortality throughout the world. Therapeutic options to reduce symptoms, inflammatory response, or disease progression are limited. This randomized open-label trial enrolled 100 ambulatory patients with symptomatic COVID-19 in Toronto, Canada. Results indicate that icosapent ethyl (8 g daily for 3 days followed by 4 g daily for 11 days) significantly reduced high-sensitivity C-reactive protein (hs-CRP) and improved symptomatology compared with patients assigned to usual care. Specifically, the primary biomarker endpoint, change in hs-CRP, was significantly reduced by 25% among treated patients (−0.5 mg/L, interquartile range [IQR] [−6.9,0.4], within-group p = 0.011). Conversely, a non-significant 5.6% reduction was observed among usual care patients (−0.1 mg/L, IQR [−3.2,1.7], within-group p = 0.51). An unadjusted between-group primary biomarker analysis was non-significant (p = 0.082). Overall, this report provides evidence of an early anti-inflammatory effect of icosapent ethyl in a modest sample, including an initial well-tolerated loading dose, in symptomatic outpatients with COVID-19. ClinicalTrials.gov Identifier: NCT04412018.

Abstract Background Individuals with diabetes often have high levels of atherogenic lipoproteins and cholesterol reflected by elevated low-density lipoprotein cholesterol (LDL-C), non-high-density lipoprotein cholesterol (non-HDL-C), apolipoprotein B (ApoB), and LDL particle number (LDL-PN). The presence of atherosclerotic cardiovascular disease (ASCVD) increases the risk of future cardiovascular events. We evaluated the efficacy and safety of the proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitor, alirocumab, among individuals with type 2 diabetes (T2DM), high LDL-C or non-HDL-C, and established ASCVD receiving maximally tolerated statin in ODYSSEY DM-DYSLIPIDEMIA (NCT02642159) and DM-INSULIN (NCT02585778). Methods In DM-DYSLIPIDEMIA, individuals with T2DM and mixed dyslipidemia (non-HDL-C ≥ 100 mg/dL; n = 413) were randomized to open-label alirocumab 75 mg every 2 weeks (Q2W) or usual care (UC) for 24 weeks, with UC options selected before stratified randomization. In DM-INSULIN, insulin-treated individuals with T2DM (LDL-C ≥ 70 mg/dL; n = 441) were randomized in a double-blind fashion to alirocumab 75 mg Q2W or placebo for 24 weeks. Study participants also had a glycated hemoglobin

Abstract Background The SUSTAIN 6 trial demonstrated that once-weekly semaglutide (0.5 and 1.0 mg) significantly reduced major adverse cardiovascular (CV) events (MACE) vs placebo in subjects with type 2 diabetes (T2D) and high CV risk. The effects of gender, age and baseline CV risk on outcomes are important considerations for further study. Methods Subjects were grouped according to gender, age (50–65 years and > 65 years), and CV risk profile at baseline (prior myocardial infarction [MI] or stroke vs no prior MI or stroke, and established CV disease [CVD] vs CV risk factors alone, including subjects with chronic kidney disease). Time to MACE and its individual components (CV death, nonfatal MI, nonfatal stroke), hospitalization for unstable angina or heart failure, and revascularization (coronary and peripheral) were analyzed for all subgroups. Additional analyses were performed for gender and age to investigate change from baseline in HbA1c and body weight, as well as tolerability. Results A total of 3297 subjects were included. The majority of subjects (60.7%) were male; 43% were > 65 years of age; 41.5% had a history of MI or stroke; and 76.8% had established CVD. Compared with placebo, semaglutide reduced the risk of the first occurrence of MACE and each MACE component consistently across all subgroups (gender, age, and baseline CV risk profile). Revascularizations, HbA1c and body weight were also reduced consistently across all subgroups compared with placebo. Gastrointestinal adverse events in all treatment groups were more common among women than men, but rates of premature treatment discontinuation were similar for both genders. Conclusions In this post hoc analysis of SUSTAIN 6, once-weekly semaglutide vs placebo reduced the risk of MACE in all subjects included in the trial, regardless of gender, age, or baseline CV risk profile. Trial registry Clinicaltrials.gov, Identifying number: NCT01720446, Date of registration: October 29, 2012

Background Public health policies reflect concerns that certain fruit sources may not have the intended benefits and that vegetables should be preferred to fruit. We assessed the relation of fruit and vegetable sources with cardiovascular outcomes using a systematic review and meta‐analysis of prospective cohort studies. Methods and Results MEDLINE, EMBASE, and Cochrane were searched through June 3, 2019. Two independent reviewers extracted data and assessed study quality (Newcastle‐Ottawa Scale). Data were pooled (fixed effects), and heterogeneity (Cochrane‐Q and I2) and certainty of the evidence (Grading of Recommendations Assessment, Development, and Evaluation) were assessed. Eighty‐one cohorts involving 4 031 896 individuals and 125 112 cardiovascular events were included. Total fruit and vegetables, fruit, and vegetables were associated with decreased cardiovascular disease (risk ratio, 0.93 [95% CI, 0.89–0.96]; 0.91 [0.88–0.95]; and 0.94 [0.90–0.97], respectively), coronary heart disease (0.88 [0.83–0.92]; 0.88 [0.84–0.92]; and 0.92 [0.87–0.96], respectively), and stroke (0.82 [0.77–0.88], 0.82 [0.79–0.85]; and 0.88 [0.83–0.93], respectively) incidence. Total fruit and vegetables, fruit, and vegetables were associated with decreased cardiovascular disease (0.89 [0.85–0.93]; 0.88 [0.86–0.91]; and 0.87 [0.85–0.90], respectively), coronary heart disease (0.81 [0.72–0.92]; 0.86 [0.82–0.90]; and 0.86 [0.83–0.89], respectively), and stroke (0.73 [0.65–0.81]; 0.87 [0.84–0.91]; and 0.94 [0.90–0.99], respectively) mortality. There were greater benefits for citrus, 100% fruit juice, and pommes among fruit sources and allium, carrots, cruciferous, and green leafy among vegetable sources. No sources showed an adverse association. The certainty of the evidence was “very low” to “moderate,” with the highest for total fruit and/or vegetables, pommes fruit, and green leafy vegetables. Conclusions Fruits and vegetables are associated with cardiovascular benefit, with some sources associated with greater benefit and none showing an adverse association. Registration URL: https://www.clini​caltr​ials.gov; Unique identifier: NCT03394339.

Context: We examined if empagliflozin was associated with modulation of cardiac autonomic tone among subjects with type 2 diabetes and stable coronary artery disease (CAD) relative to placebo. Methods: Using ambulatory 24-h Holter electrocardiographic data prospectively collected from a randomized trial, we compared changes in heart rate variability (HRV) parameters between empagliflozin- and placebo-assigned subjects over a follow-up period of 6 months. Measured HRV domains included: standard deviation (SD) of NN intervals (SDNN), SD of average NN intervals per 5-min (SDANN), root mean square of successive RR interval differences (RMSSD), % successive NN intervals differing >50 ms (ms) (pNN50), low frequency (LF), high frequency (HF) and the LF/HF ratio (LF:HF). Differences in HRV parameters between the 2 groups were compared with analysis of covariance (ANCOVA). Statistical measures of significance were reported as adjusted differences between the 2 groups and their corresponding 95% confidence intervals. Results: Sixty-six subjects completed 24-h Holter monitoring at baseline and 6-months. Over 6 months, the change in HRV was similar between subjects treated with empagliflozin vs. placebo for the following parameters: RMSSD -1.2 ms (-6.0 to 3.6 ms); pNN50 0.5% (-2.6 to 3.6%); VLF -907.8 ms2 (-2388.8 to 573.1 ms2); LF -341 ms2 (-878.7 to 196.7 ms2); HF -33.8 ms2 (-111.1 to 43.5 ms2); LF:HF -0.1 (-0.4 to 0.2). Subjects who received placebo experienced an increase in SDNN 18.6 ms (2.8–34.3 ms) and SDANN 20.2 ms (3.2–37.3 ms) relative to those treated with empagliflozin. Conclusion: Compared to placebo, empagliflozin did not result in changes in autonomic tone among individuals with type 2 diabetes and stable coronary artery disease.

Abstract Background A number of non‐low‐density lipoprotein cholesterol lipid abnormalities are associated with type 2 diabetes and insulin resistance, which may lead practitioners to use medications targeting these abnormal lipid fractions despite a lack of evidence or guideline recommendations. Methods and Results Among 382 921 US patients with type 2 diabetes (69% with cardiovascular disease, 76% on a statin), 95 995 (26%) were on some nonstatin lipid‐lowering medication—19 265 (5%) on niacin, 32 919 (9%) on a fibrate and 69 513 (18%) on fish oil. Use of all three medications was stable over time and higher in patients with cardiovascular disease and with higher triglyceride levels, although even among patients with triglyceride levels

Abstract Background Although the number of antihyperglycemic agents has expanded significantly, sulfonylureas (in particular gliclazide) remain an important option because of a variety of patient and health system factors. The large, real world, observational, and international EASYDia trial evaluated the effectiveness of gliclazide modified release (MR) 60 mg in individuals with type 2 diabetes with a broad range of diabetes history, body mass index (BMI) and background antihyperglycemic treatment. Methods A total of 7170 participants from eight countries, age ≥ 35 years with HbA1c ≥ 7.5% and not treated with insulin, were prescribed 30–120 mg of gliclazide MR 60 mg once daily. HbA1c goals were individualized and dosing uptitrated, as required, over the 6-month long study. In this post hoc subanalysis, efficacy endpoints were analyzed according to stratified baseline HbA1c levels, weight and glucose-lowering regimens. Episodes of hypoglycemia requiring assistance were documented. Results At baseline, mean age was 58.9 years, HbA1c 8.8%, BMI 30.1 kg/m2, and diabetes duration 5.1 years. At study end, clinically significant HbA1c improvements (mean change − 1.78%) were noted across all baseline HbA1c strata (> 7.0 to ≤ 8.0%, > 8.0 to ≤ 9.0%, > 9.0 to ≤ 10.0%, and > 10.0%), BMI classifications (18.5 to

Abstract Background Type 2 diabetes mellitus (T2DM) is often associated with mixed dyslipidaemia, where non-high-density lipoprotein cholesterol (non-HDL-C) levels may more closely align with cardiovascular risk than low-density lipoprotein cholesterol (LDL-C). We describe the design and rationale of the ODYSSEY DM-DYSLIPIDEMIA study that assesses the efficacy and safety of alirocumab, a proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitor, versus lipid-lowering usual care in individuals with T2DM and mixed dyslipidaemia at high cardiovascular risk with non-HDL-C inadequately controlled despite maximally tolerated statin therapy. For the first time, atherogenic cholesterol-lowering with a PCSK9 inhibitor will be assessed with non-HDL-C as the primary endpoint with usual care as the comparator. Methods DM-DYSLIPIDEMIA is a Phase 3b/4, randomised, open-label, parallel group, multinational study that planned to enrol 420 individuals. Main inclusion criteria were T2DM and mixed dyslipidaemia (non-HDL-C ≥100 mg/dl [≥2.59 mmol/l], and triglycerides ≥150 and

Background Sugar‐sweetened beverages are associated with hypertension. We assessed the relation of important food sources of fructose‐containing sugars with incident hypertension using a systematic review and meta‐analysis of prospective cohort studies. Methods and Results We searched MEDLINE, EMBASE, and Cochrane (through December week 2, 2018) for eligible studies. For each food source, natural log‐transformed risk ratios (RRs) for incident hypertension were pooled using pair‐wise meta‐analysis and linear and nonlinear dose‐response meta‐analyses. Certainty in our evidence was assessed using Grading of Recommendations Assessment, Development and Evaluation. We identified 26 reports, including 15 prospective cohorts (930 677 participants; 363 459 cases). Sugar‐sweetened beverages showed harmful (RRper‐355‐mL, 1.10 [95% CI, 1.08, 1.12]) whereas fruit (RRper‐240‐g, 0.94 [95% CI, 0.96, 0.99]) and yogurt showed protective associations (RRper‐125‐g, 0.95 [95% CI, 0.94, 0.97]) with incident hypertension throughout the dose range. One hundred percent fruit juice showed a protective association only at moderate doses (RRat‐100‐mL, 0.97 [95% CI, 0.94, 0.99]). The pair‐wise protective association of dairy desserts was not supported by linear dose‐response analysis. Fruit drinks or sweet snacks were not associated with hypertension. Certainty of the evidence was “low” for sugar‐sweetened beverages, 100% fruit juice, fruit, and yogurt and “very low” for fruit drinks, sweet snacks, and dairy desserts. Conclusions The harmful association between sugar‐sweetened beverages and hypertension does not extend to other important food sources of fructose‐containing sugars. Further research is needed to improve our estimates and better understand the dose‐response relationship between food sources of fructose‐containing sugars and hypertension. Registration URL: https://www.clinicaltrials.gov/. Unique identifier: NCT02702375.

Background It is not clear whether the effects of lipid‐lowering or antihypertensive medications are influenced by adherence to healthy lifestyle factors. We assessed the effects of both drug interventions in subgroups by the number of healthy lifestyle factors in participants in the HOPE‐3 (Heart Outcomes Prevention Evaluation) trial. Methods and Results In this primary prevention trial, 4 healthy lifestyle factors (nonsmoking status, physical activity, optimal body weight, and healthy diet) were recorded in 12 521 participants who were at intermediate risk of cardiovascular disease (CVD) and were randomized to rosuvastatin, candesartan/hydrochlorothiazide, their combination, or matched placebos. Median follow‐up was 5.6 years. The outcome was a composite of CVD events. Adjusted hazard ratios (HRs) and 95% confidence intervals (CIs) were estimated using Cox regression models. Participants with ≥2 healthy lifestyle factors had a lower rate of CVD compared with those with fewer factors (HR: 0.85; 95% CI, 0.73–1.00). Rosuvastatin reduced CVD events in participants with ≥2 healthy lifestyle factors (HR: 0.74; 95% CI, 0.62–0.90) and in participants with

BackgroundThere is a heightened interest in plant‐based diets for cardiovascular disease prevention. Although plant protein is thought to mediate such prevention through modifying blood lipids, the effect of plant protein in specific substitution for animal protein on blood lipids remains unclear. To assess the effect of this substitution on established lipid targets for cardiovascular risk reduction, we conducted a systematic review and meta‐analysis of randomized controlled trials using the Grading of Recommendations Assessment, Development, and Evaluation system. Methods and ResultsMEDLINE, EMBASE, and the Cochrane Registry were searched through September 9, 2017. We included randomized controlled trials of ≥3 weeks comparing the effect of plant protein in substitution for animal protein on low‐density lipoprotein cholesterol, non–high‐density lipoprotein cholesterol, and apolipoprotein B. Two independent reviewers extracted relevant data and assessed risk of bias. Data were pooled by the generic inverse variance method and expressed as mean differences with 95% confidence intervals. Heterogeneity was assessed (Cochran Q statistic) and quantified (I2 statistic). The overall quality (certainty) of the evidence was assessed using the Grading of Recommendations Assessment, Development, and Evaluation system. One‐hundred twelve randomized controlled trials met the eligibility criteria. Plant protein in substitution for animal protein decreased low‐density lipoprotein cholesterol by 0.16 mmol/L (95% confidence interval, −0.20 to −0.12 mmol/L; P

BackgroundNon‐high‐density lipoprotein cholesterol (non‐HDL‐C) and apolipoprotein (apo) B are better predictors of atherosclerotic cardiovascular disease risk than low‐density lipoprotein cholesterol alone. US and European lipid management guidelines support non‐HDL‐C and apoB as targets for lipid‐lowering therapy. Methods and ResultsThis analysis evaluated the efficacy of alirocumab, a proprotein convertase subtilisin/kexin type 9 inhibitor, on non‐HDL‐C and apoB. Data were derived from 4983 patients enrolled in 10 randomized, placebo‐ or ezetimibe‐controlled Phase 3 ODYSSEY trials. Primary end point for this pooled analysis was percent reduction in non‐HDL‐C and apoB at Week 24; secondary end points included the percentage of patients achieving guideline‐directed treatment goals (National Lipid Association guidelines: non‐HDL‐C 70% of alirocumab‐treated patients on background statin achieved non‐HDL‐C

BackgroundAldosterone may have adverse effects in the myocardium and vasculature. Treatment with an aldosterone antagonist reduces cardiovascular risk in patients with acute myocardial infarction complicated by heart failure (HF) and left ventricular systolic dysfunction. However, most patients with acute coronary syndrome do not have advanced HF. Among such patients, it is unknown whether aldosterone predicts cardiovascular risk. Methods and ResultsTo address this question, we examined data from the dal‐OUTCOMES trial that compared the cholesteryl ester transfer protein inhibitor dalcetrapib with placebo, beginning 4 to 12 weeks after an index acute coronary syndrome. Patients with New York Heart Association class II (with LVEF